ObjectiveTo investigate the effect of mucin 1 (MUC1) on the proliferation and apoptosis of nasopharyngeal carcinoma (NPC) and its regulatory mechanism. MethodsThe 60 NPC and paired para-cancer normal tissues were collected from October 2020 to July 2021 in Quanzhou First Hospital. The expression of MUC1 was measured by real-time quantitative PCR (qPCR) in the patients with PNC. The 5-8F and HNE1 cells were transfected with siRNA control (si-control) or siRNA targeting MUC1 (si-MUC1). Cell proliferation was analyzed by cell counting kit-8 and colony formation assay, and apoptosis was analyzed by flow cytometry analysis in the 5-8F and HNE1 cells. The qPCR and ELISA were executed to analyze the levels of TNF-α and IL-6. Western blot was performed to measure the expression of MUC1, NF-кB and apoptosis-related proteins (Bax and Bcl-2). ResultsThe expression of MUC1 was up-regulated in the NPC tissues, and NPC patients with the high MUC1 expression were inclined to EBV infection, growth and metastasis of NPC. Loss of MUC1 restrained malignant features, including the proliferation and apoptosis, downregulated the expression of p-IкB、p-P65 and Bcl-2 and upregulated the expression of Bax in the NPC cells. ConclusionDownregulation of MUC1 restrained biological characteristics of malignancy, including cell proliferation and apoptosis, by inactivating NF-κB signaling pathway in NPC.

Caspase-2, a highly conserved member of the caspase family, is considered an initiator caspase that triggers apoptosis in response to some cellular stresses. Previous studies suggest that an intracellular multi-protein complex PIDDosome, induced by genotoxic stress, serves as a platform for caspase-2 activation. Due to caspase-2's inability to process effector caspases, however, the mechanism underlying caspase-2-mediated cell death upon PIDDosome activation remains unclear. Here, we conducted an unbiased genome-wide genetic screen and identified that the Bcl2 family protein BID is required for PIDDosome-induced, caspase-2-mediated apoptosis. PIDDosome-activated caspase-2 directly and functionally processes BID to signal the mitochondrial pathway for apoptosis induction. In addition, a designed chemical screen identified a compound, HUHS015, which specifically activates caspase-2-mediated apoptosis. HUHS015-stimulated apoptosis also requires BID but is independent of the PIDDosome. Through extensive structure-activity relationship efforts, we identified a derivative with a potency of ~60 nmol/L in activating caspase-2-mediated apoptosis. The HUHS015-series of compounds act as efficient agonists that directly target the interdomain linker in caspase-2, representing a new mode of initiator caspase activation. Human and mouse caspase-2 differ in two crucial residues in the linker, rendering a selectivity of the agonists for human caspase-2. The caspase-2 agonists are valuable tools to explore the physiological roles of caspase-2-mediated cell death and a base for developing small-molecule drugs for relevant diseases.
Caspase 2/genetics* ; Humans ; BH3 Interacting Domain Death Agonist Protein/metabolism* ; Apoptosis/drug effects* ; Death Domain Receptor Signaling Adaptor Proteins/metabolism* ; Animals ; Mice ; Cysteine Endopeptidases

Objective: To investigate and elucidate the clinicopathological and prognostic characteristics of SMARCA4-deficient non-small cell lung cancer. Methods: The clinicopathological and prognostic data were collected in 127 patients with SMARCA4-deficient non-small cell lung cancer diagnosed in Shanghai Pulmonary Hospital, Shanghai, China from January 2020 to March 2022. The variation and expression of biomarkers related to treatment were retrospectively reviewed. Results: One hundred and twenty-seven patients were eligible for enrollment. Among them 120 patients (94.5%) were male and 7 cases (5.5%) were female, while the average age was 63 years (range 42-80 years). There were 41 cases (32.3%) of stage Ⅰ cancer, 23 cases (18.1%) of stage Ⅱ, 31 cases (24.4%) of stage Ⅲ and 32 cases (25.2%) of stage Ⅳ. SMARCA4 expression detected by immunohistochemistry was completely absent in 117 cases (92.1%) and partially absent in 10 cases (7.9%). PD-L1 immunohistochemical analyses were performed on 107 cases. PD-L1 was negative, weakly positive and strongly positive in 49.5% (53/107), 26.2% (28/107) and 24.3% (26/107) of the cases, respectively. Twenty-one cases showed gene alterations (21/104, 20.2%). The KRAS gene alternation (n=10) was most common. Mutant-type SMARCA4-deficient non-small cell lung cancer was more commonly detected in females, and was associated with positive lymph nodes and advanced clinical stage (P<0.01). Univariate survival analysis showed that advanced clinical stage was a poor prognosis factor, and vascular invasion was a poor predictor of progression-free survival in patients with surgical resection. Conclusions: SMARCA4-deficient non-small cell lung cancer is a rare tumor with poor prognosis, and often occurs in elderly male patients. However, SMARCA4-deficient non-small cell lung cancers with gene mutations are often seen in female patients. Vascular invasion is a prognostic factor for disease progression or recurrence in patients with resectable tumor. Early detection and access to treatment are important for improving patient survivals.
Humans ; Male ; Female ; Aged ; Adult ; Middle Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung/pathology* ; B7-H1 Antigen/metabolism* ; Lung Neoplasms/pathology* ; Retrospective Studies ; China ; Prognosis ; Biomarkers, Tumor/analysis* ; DNA Helicases/genetics* ; Nuclear Proteins/genetics* ; Transcription Factors/genetics*

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC₅₀ = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC₅₀ = 1.513 μmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 μg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 ( 5) and AZD5099 ( 6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 ( 6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 μg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure-activity relationships of the compounds were also studied.

Heart failure (HF),a chronic progressive disease,is a global health problem and the leading cause of deaths in the global population.The pathophysiological abnormalities of HF mainly include abnormal cardiac structure (myocardium and valves),disturbance of electrophysiological activities,and weakened myocardial contractility.In addition to drug therapy and heart transplantation,interventional therapies can be employed for advanced-stage HF,including transcatheter interventions and mechanical circulatory assist devices.This article introduces the devices used for advanced HF that have been marketed or certified as innovative or breakthrough devices around the world and summarizes the research status and prospects the trend in this field.As diversified combinations of HF devices are used for the treatment of advanced HF,considerations regarding individualized HF therapy,risk-benefit evaluation on device design,medical insurance payment,post-market supervision system,and protection of intellectual property rights of high-end technology are needed,which will boost the development of the technology and industry and benefit the patients.
Humans ; Heart-Assist Devices ; Heart Failure/therapy* ; Heart Transplantation ; Myocardium ; Chronic Disease

Objective:To analyze the postoperative paravertebral muscle degeneration and its correlations with health related quality of life (HRQL) in patients undergoing minimally invasive surgery-transforaminal lumbar interbody fusion (MIS-TLIF).Methods:The clinical data of the 50 patients were retrospectively analyzed who had undergone single-segmental MIS-TLIF at Department of Spinal Cord Surgery, The People's Hospital of Henan Province from January 2019 to December 2021. The relative volumes of lumbar posterior muscle (LM), the relative volumes of the psoas major (PM), and the rates of fatty degeneration (FD) of the fused segment and its adjacent segments were compared respectively between preoperation, 6 and 12 months postoperation. The correlations were analyzed between the HRQL scores [visual analog scale (VAS) for pain and Oswestry disability index (ODI)] and the relative LM volumes, the relative PM volumes, and the FD rates of the fused segment and its adjacent segments at 12 months postoperation.Results:Compared with the preoperative values, the relative LM volumes and the relative PM volumes of the fused segment and its adjacent segments at 6 and 12 months postoperation were significantly reduced while the FD rates significantly increased. However, the FD rate of the fused segment at 12 months postoperation (20.6% ± 6.1%) was significantly lower than that at 6 months postoperation (29.7% ± 8.2%) ( P < 0.05). The VAS score was strongly negatively or positively correlated with the relative LM volume ( r = -0.819, P < 0.001) and the FD rate ( r = 0.86, P < 0.001) of the fused segment, and moderately negatively correlated with the relative PM volume ( r = -0.435, P = 0.016). The ODI index was moderately negatively correlated with the relative LM volume ( r = -0.512, P = 0.004) and the relative PM volume ( r = -0.402, P = 0.020) of the fused segment, but moderately positively correlated with the FD rate of the fused segment ( r = 0.565, P = 0.001). There was a moderate negative correlation between the ODI index and the relative LM volume of the adjacent segments ( r = -0.478, P = 0.012). Conclusions:After MIS-TLIF, the volume of the paravertebral muscles decreases and the dorsal muscles develop fatty degeneration. The improvement of LM fatty degeneration may be observed by 12-month follow-up in the fused segment, but not in the adjacent segments. The LM volume and the FD rate of the fused segment are the most closely related to the postoperative HRQL.

Objective: To investigate the clinicopathological features, diagnostic criteria and differential diagnosis of primary salivary gland-type duct carcinoma of lung(LSDC). Methods: Two patients with LSDC after surgical resection in Shanghai Pulmonary Hospital from 2020 to 2021 were included; their clinical parameters as well as pathological, immunohistochemical and molecular characteristics of the tumors were analyzed. The relevant literature was also reviewed. Results: Both patients were male, aged 49(case 1) and 64(case 2) years, respectively, and with a history of smoking. The chest computed tomography scan showed both lesions to be centrally located. Gross examination showed the maximum diameters were 16 mm and 35 mm, respectively. The histomorphology of LSDC resembled ductal carcinoma of breast, with intraductal islands of neoplastic cells, which also formed solid nests, papillary, micropapillary and cribriform structures. There was frequent accompanying comedo-like necrosis. The neoplasm cells were markedly heteromorphic, possessing large irregular nuclei with prominent nucleoli, abundant eosinophilic or clear cytoplasm, and mitotic figures were common. Both cases of LSDC were immunoreactive for CKpan, CK7, AR, HER2 staining was (2+) and were negative for TTF1, Napsin A, p40, GATA3, mammaglobin, GCDFP15, SOX10, PSA, P504S, ER, PR, vimentin, S-100, SMA, CK5/6 and p63. The tumor showed double-layer cell structure of the duct, and some basal cells/myoepithelial cells expressed p40 and CK5/6. Case 1 had no gene mutation while case 2 harbored TP53 and KMT2A gene mutation detected by next generation sequencing. Conclusions: LSDC is a very rare and highly aggressive salivary-type malignant tumor. The postoperative diagnosis mainly depends on histopathology and immunohistochemistry, attention should be paid to differential diagnosis to prevent missed diagnosis.
Biomarkers, Tumor/analysis* ; Breast Neoplasms ; Carcinoma, Ductal, Breast ; Child, Preschool ; China ; Humans ; Lung ; Male ; Salivary Ducts/chemistry*

Objective To evaluate the risk of hearing loss of assembly workers in an automobile manufacturing factory. Methods An 8-hour equivalent sound level monitoring was carried out for assembly posts in an automobile factory. The risk of noise-induced hearing loss of assembly workers was measured using the method specified in ISO 1999:2013(E). The risk of noise-induced hearing loss was assessed in a graded manner according to the Guidelines for the Management of Occupational Disease Hazards from Noise. The results were statistically analyzed using Pearson correlation analysis. Results The average 8-hour equivalent sound level of the assembly work post in this automobile manufacturing factory was 89.5 dB (A). At 4000 Hz, the hearing loss N₅₀ (dB) of assembly workers reached the maximum. The longer the exposure time, the higher the risk of high-frequency standard hearing threshold shift. The risk of high-frequency standard hearing threshold shift was at a relatively high level at 30 years of work, while the risk of noise deafness reached a higher level after 40 years of work. Conclusion The 8-hour equivalent sound level (L_EX,8h) of assembly workers in the automobile factory exceeds the occupational exposure limit. With the increase of exposure years, the risk of high-frequency standard hearing threshold shift and noise deafness increases.

OBJECTIVE: To compare treatment effect of monolateral and circular external fixator in infectious tibial nonunion and to explore external fixation structure with better osteogenic ability and fewer complications. METHODS: A retrospective analysis was performed on 150 patients with infectious tibial nonunion admitted from January 2010 to December 2014. Patients who met the inclusion and exclusion criteria were divided into monolateral fixator group and circular fixator group according to the type of external fixation. Demographic and perioperative data of the two groups were collected. New bone quality was assessed by pixels ratio, treatment effect was assessed by complications. Notes for treatment was explored by case analysis. RESULTS: A total of 64 patients with infectious mid-tibial nonunion were included, 26 in monolateral fixator group and 38 in circular fixator group. There was no difference in demographic data between two groups. The pixel ratio of new bone between two groups was from 0.91 to 0.97 with an average of (0.94±0.03), and from 0.93 to 0.97 with an average of(0.95±0.02), respectively, with no statistical significance (P>0.05). The external fixation index was from 34.1 to 50.6 with an average of (42.3±8.3) days /cm in monolateral fixator group and from 44.5 to 56.1 with an average of (45.8±10.3) days/cm in the circular fixator group, and the difference was not statistically significant (P>0.05). There were 7 cases (26.9%) of complications in monolateral fixator group and 5 cases (13.2%) in circular fixator group, the difference was not statistically significant (P>0.05), but 5 cases of foot ptosis in monolateral fixator group and none in circular fixator group. The time of weight bearing in monolateral fixator group was later than that in circular fixator group, and the difference was statistically significant (P<0.05). CONCLUSION Monolateral and circular fixators can achieve equivalent bone formation in the treatment of infected tibial nonunion. Circular fixator is recommended for patients with severe osteoporosis or concomitant medical diseases requiring early weight bearing. Hydroxyapatite coated screws are recommended if a monolateral external fixator is selected when the expected enlarged length is long and the fixation time is long and close monitoring of the ankle movement is required to avoid foot droop.
Humans ; Tibial Fractures/surgery* ; Retrospective Studies ; External Fixators ; Tibia/surgery* ; Treatment Outcome ; Hydroxyapatites

OBJECTIVE: This paper is aimed at investigating the efficacy of combining internal fixation using prefabricated rib-locking titanium plate with ultrasound-guided thoracic paravertebral nerve blockade in treating multiple rib fractures among the elderly. METHODS: Retrospective analysis of 221 elderly patients with multiple rib fractures treated from February 2016 to November 2020. According to whether surgery was performed, they were divided into the plate-blockage combination group (surgical group, 102 cases) and conservative treatment group (non-surgical group, 119 cases). The surgical group consisted of 58 males and 44 females aged from 60 to 85 years old, with an average of (67.2±3.6 ) years old, who suffered from 3 to 12 rib fractures with an average of (5.3±2.1) fractures. The non-surgical group consisted of 66 males and 53 females aged from 60 to 84 years old with an average of (66.8±3.2) years old, who suffered from 2 to 11 rib fractures with an average of(6.1±2.3) fractures. The clinical data, efficacies observed, and complications associated with both groups were compared and analyzed. RESULTS: There was no significant difference in preoperative clinical data between two groups (P>0.05), and all patients were discharged smoothly. Pulmonary infection (P=0.028), atelectasis (P=0.032), respiratory failure (P=0.026), time to get out of bed (P=0.040), time to fracture healing (P=0.035), length of hospital stay in the operation group (P=0.043), visual analogue scale (VAS) at 3 days (P=0.028), 5 days(P=0.032), and 7 days(P=0.019), maximal voluntary ventilation (MVV) at 3 months after surgery (P=0.042), forced expiratory volume in one second (FEV1)(P=0.035), and maximal voluntary ventilation at 6 months, the maximal voluntary ventilation(MVV)(P=0.021) and forced FEV1(P=0.026) were all significantly better than those in non-surgical treatment group. CONCLUSION For elderly patients with severe multiple rib fractures, the proposed plate-blockade combination can timely and effectively relieve pain, restore thoracic stability, shorten hospital stay, and reduce the incidence of complications such as pulmonary infections and acute respiratory distress syndrome(ARDS) compared with non-surgical treatments. Prefabricated rib-locking titanium plates have proved to demonstrate high clinical efficacy in treating multiple rib fractures among the elderly.
Male ; Female ; Humans ; Aged ; Middle Aged ; Aged, 80 and over ; Rib Fractures/etiology* ; Titanium ; Retrospective Studies ; Bone Plates/adverse effects* ; Fracture Fixation, Internal/adverse effects* ; Treatment Outcome ; Ultrasonography, Interventional/adverse effects* ; Nerve Block/adverse effects* ; Ribs